Interstitial cystitis (IC), also referred to as Painful Bladder Syndrome (PBS) is a condition with significant impact on quality of life. Therapy with oral Cyclosporine A (CyA) has shown some efficacy in this condition and is a fifth line therapy in the Guidelines of the American Urological Association. However CyA is a toxic drug with known nephrotoxicity and potential for hypertension, infection and neurotoxicity. While CyA is an immunosuppressive drug, it's target of action, calcineurin, is also present in neural cells suggesting that the effect of CyA on the symptoms of IC may be neurally modulated as well. We propose a prospective open label study of CyA in patients with IC with careful clinical monitoring of efficacy, features of disease (UPOINT phenotype) that leads to treatment success, monitoring of drug levels, detailed monitoring of renal function, monitoring of changes in nerve function and measuring changes in inflammatory mediators in the blood and urine that indicate successful outcomes of cyclosporine treatment. Thirty adults with IC/PBS who have failed at least 2 other classes of medical therapy will be enrolled in an open label 3 month trial of oral CyA, starting at 3 mg/kg/day in 2 divided doses. Patients will be assessed pretreatment, at 3 months and 1-2 months after stopping. We will first examine the clinical efficacy and side effects of cyclosporine treatment in patients with IC/PBS refractory to first line therapies. Patients will be assessed wit C2 blood levels for dose adjustment. Renal function will be assessed with a nuclear GFR's. Patients will be clinically phenotyped with the validated UPOINT system and clinical outcomes correlated to the phenotype. We will then measure the effects of cyclosporine treatment on current perception and pain threshold using a Neurometer before, during and after treatment. Hyperalgesia will be assessed for sensation perception and pain threshold at 3 frequencies that measure function of 3 nerve types (C, A-delta, A-beta fibers). We expect symptom improvement to correlate with reduction in hyperalgesia, especially in the C fibers. Finally, we will identify changes in inflammatory mediators in the blood and urine of IC/PBS patients that indicate successful outcomes of cyclosporine treatment. RNA and protein will be extracted from blood and urine samples before, during and after therapy. Gene expression and protein signatures will be compared between patients pretreatment and 15 normal controls to identify candidate biomarkers. ELISA will test protein levels of inflammatory mediators and proteins that have been shown to be increased in the urine of IC/PBS. These genes and proteins will be following during and after therapy and changes correlated with degree of clinical improvement. We hope to show that CyA can be an effective therapy for recalcitrant IC/PBS which can be safely administered with appropriate monitoring and identify which patients benefit most from treatment